Abstract

Background

Alternative gene transcript splicing permits a single gene to produce multiple proteins
with varied functions. Bioinformatic investigations have identified numerous splice
variants, but whether these transcripts are translated to functional proteins and
the physiological significance of these alternative proteins are largely unknown.
Through direct identification of splice variants associated with disease states, we
can begin to address these questions and to elucidate their roles in disease predisposition
and pathophysiology. This work specifically sought to identify disease-associated
alternative splicing patterns in ion channel genes by comprehensively screening affected
brain tissue collected from patients with mesial temporal lobe epilepsy and Alzheimer's
disease. New technology permitting the screening of alternative splice variants in
microarray format was employed. Real time quantitative PCR was used to verify observed
splice variant patterns.

Results

This work shows for the first time that two common neurological conditions are associated
with extensive changes in gene splicing, with 25% and 12% of the genes considered
having significant changes in splicing patterns associated with mesial temporal lobe
epilepsy and Alzheimer's disease, respectively. Furthermore, these changes were found
to exhibit unique and consistent patterns within the disease groups.

Conclusion

This work has identified a set of disease-associated, alternatively spliced gene products
that represent high priorities for detailed functional investigations into how these
changes impact the pathophysiology of mesial temporal lobe epilepsy and Alzheimer's
disease.